Studies in this laboratory are designed to elucidate the role of DNA repair processes in carcinogenesis and in neurodegeneration. We had previously obtained evidence that Alzheimer disease cells have defective nucleotide excision repair of DNA damaged by free radicals. This research grew out of work on xeroderma pigmentosum, an inherited disease in which cells are unable to conduct nucleotide excision repair of damaged DNA. As a result of this inability, patients with xeroderma pigmentosum are at a very high risk of developing sunlight-induced skin cancers, and some patients also experience degeneration of the nervous system which results from the patients' inability to repair free radical-induced damage to their neuronal DNA. We hope to elucidate the specific free radical-induced lesion(s) which Alzheimer disease and xeroderma pigmentosum cells cannot repair. To accomplish these goals, we have developed methods to place certain types of DNA damage into plasmids and into DNA oligonucleotides, and we are able to test the cells for their ability to repair the damage. The use of these assays is expected to enable us to identify and study the DNA-repair defects in Alzheimer disease and in diseases with an increased incidence of cancer. We have found an oxidative lesion, 8,5'-cyclo-2'-deoxyadenosine (cyclo-dA), that requires nucleotide excision repair, and we have shown that xeroderma pigmentosum cells are deficient in its repair. With Dr. Kurt Randerath, and using his 32P-postlabeling chromatography assay, we have shown that cyclo-dA is present in all rat organs, including brain. We have reported the first autopsy of a patient with both xeroderma pigmentosum and Cockayne syndrome. He was the ninth confirmed patient with this clinical combination of two rare disorders.